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1.
Am J Hum Genet ; 91(2): 358-64, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22795537

RESUMO

Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.


Assuntos
Anormalidades Múltiplas/genética , Transtornos do Crescimento/genética , Hipertricose/congênito , Proteína de Leucina Linfoide-Mieloide/genética , Anormalidades Múltiplas/patologia , Sequência de Bases , Exoma/genética , Componentes do Gene , Transtornos do Crescimento/patologia , Haploinsuficiência/genética , Histona-Lisina N-Metiltransferase , Humanos , Hipertricose/genética , Hipertricose/patologia , Dados de Sequência Molecular , Mutação/genética , Análise de Sequência de DNA
2.
Neuron ; 52(5): 767-74, 2006 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-17145499

RESUMO

Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.


Assuntos
Mutação/fisiologia , Neuralgia/genética , Canais de Sódio/genética , Canais de Sódio/fisiologia , Alelos , Sequência de Aminoácidos , Analgésicos não Narcóticos/farmacologia , Carbamazepina/farmacologia , Linhagem Celular , Mapeamento Cromossômico , Clonagem Molecular , Análise Mutacional de DNA , Eletrofisiologia , Ligação Genética/fisiologia , Variação Genética , Genótipo , Humanos , Dados de Sequência Molecular , Canal de Sódio Disparado por Voltagem NAV1.7 , Neuralgia/fisiopatologia , Técnicas de Patch-Clamp , Linhagem , Fenótipo , Bloqueadores dos Canais de Sódio , Canais de Sódio/efeitos dos fármacos , Transfecção
3.
Nat Genet ; 44(6): 639-41, 2012 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-22544363

RESUMO

We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Proteínas Nucleares/genética , Idoso , Envelhecimento , Cromossomos Humanos Par 17 , Fácies , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Síndrome de Smith-Magenis , Síndrome
4.
Nat Genet ; 43(4): 303-5, 2011 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-21378985

RESUMO

We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.


Assuntos
Síndrome de Hajdu-Cheney/genética , Mutação , Receptor Notch2/genética , Alelos , Sequência de Bases , Análise Mutacional de DNA , DNA Complementar/genética , Éxons , Feminino , Síndrome de Hajdu-Cheney/metabolismo , Síndrome de Hajdu-Cheney/patologia , Humanos , Masculino , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Linhagem , Sinais Direcionadores de Proteínas/genética , Receptor Notch2/metabolismo
5.
Eur J Pain ; 14(9): 944-50, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20385509

RESUMO

Dominant gain-of-function mutations that hyperpolarize activation of the Na(v)1.7 sodium channel have been linked to inherited erythromelalgia (IEM), a disorder characterized by severe pain and redness in the feet and hands in response to mild warmth. Pharmacotherapy remains largely ineffective for IEM patients with cooling and avoidance of triggers being the most reliable methods to relieve pain. We now report a 5 year old patient with pain precipitated by warmth, together with redness in her hands and feet. Her pain episodes were first reported at 12 months, and by the age of 15-16 months were triggered by sitting as well as heat. Pain has been severe, inducing self-mutilation, with limited relief from drug treatment. Our analysis of the patient's genomic DNA identified a novel Na(v)1.7 mutation which replaces isoleucine 234 by threonine (I234T) within domain I/S4-S5 linker. Whole-cell voltage-clamp analysis shows a I234T-induced shift of -18 mV in the voltage-dependence of activation, accelerated time-to-peak, slowed deactivation and enhanced responses to slow ramp depolarizations, together with a -21 mV shift in the voltage-dependence of slow-inactivation. Our data show that I234T induces the largest activation shift for Na(v)1.7 mutations reported thus far. Although enhanced slow-inactivation may attenuate the gain-of-function of the I234T mutation, the shift in activation appears to be dominant, and is consistent with the severe pain symptoms reported in this patient.


Assuntos
Dor Intratável/genética , Dor Intratável/metabolismo , Índice de Gravidade de Doença , Canais de Sódio/genética , Substituição de Aminoácidos/genética , Pré-Escolar , Eritromelalgia/diagnóstico , Eritromelalgia/genética , Eritromelalgia/metabolismo , Feminino , Células HEK293 , Humanos , Isoleucina/genética , Canal de Sódio Disparado por Voltagem NAV1.7 , Dor Intratável/diagnóstico , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Treonina/genética
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